Recombinant AAV as a Platform for Translating the Therapeutic Potential of RNA Interference

Abstract

RNA interference has become a ubiquitous biological tool, and is being harnessed for therapeutic purposes as well. Therapeutic posttranscriptional gene silencing takes advantage of the endogenous RNAi pathway through delivery of either chemically synthesized siRNAs, or transgenes expressing hairpin-based inhibitory RNAs (e.g., shRNAs and artificial miRNAs). RNAi has expanded the field of viral gene therapy from gene replacement to gene knockdown. Here, we review various noncoding RNAs such as shRNAs, miRNAs, and miRNA decoys which can be utilized for therapeutic applications when expressed from recombinant adeno-associated vectors (AAV), and present examples of their basic design. In addition the basis of exploiting cellular miRNA profiles for detargeting AAV expression from specific cells is described. Finally, an overview of AAV-mediated RNAi preclinical studies is presented, and current RNAi-based clinical trials are reviewed.

Induction of Sustained Hypercholesterolemia by Single Adeno-Associated Virus–Mediated Gene Transfer of Mutant hPCSK9

“…19,20 These features make AAV vectors a successful gene therapy approach for reverting genetic dysfunctions in preclinical models, 21,22 and to date, these vectors have been tested as a tool for reverting genetic disease. However, the same rationale could be used to cause a disease, generating a model for experimental analysis, but to our knowledge, this alternative application has not been tested to date.…”

Nano-sized carriers in gene therapy for renal fibrosisin vivo

“…To overcome this drawback of the adenoviral vector, AAV vectors have been developed [58]. AAV vectors are single-stranded, non-enveloped DNA viral vectors, 18–26 nm in diameter, with a genome of 4–5 kb [56,58,59]. AAV vectors can also transfect genes into both dividing and non-dividing cells, and may incorporate genes into the host genome.…”

Nano-sized carriers in gene therapy for peritoneal fibrosisin vivo

“…AAVs are single-stranded, non-enveloped DNA viral vectors 18–26 nm in diameter, with a genome of 4–5 kb [46,48,49]. AAVs can deliver transgenes into both dividing and non-dividing cells, and can incorporate their transgenes into the host genome [46,48,49].…”

“…AAVs can deliver transgenes into both dividing and non-dividing cells, and can incorporate their transgenes into the host genome [46,48,49]. Intraperitoneal administration of AAVs expressing decorin significantly inhibited peritoneal fibrosis, associated with preserved peritoneal cell size, decreased peritoneal thickness, and decreased expression of α-SMA in the peritoneum in a mouse peritoneal fibrosis model [37].…”